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Aim: The present research work was aimed to formulate fast disintegrating tablets (FDTs) of salbutamol sulphate (SBS) using a combination of a superdisintegrant and a subliming agent, optimize the formulation and evaluate the in vitro performance of the developed FDTs. Materials and Methods: A formulation of SBS FDT was developed using a combination of superdisintegrant - crospovidone and subliming agent - Ammonium Bicarbonate (AB) in which formulation variables, namely levels of crospovidone and Microcrystalline Cellulose (MCC):Mannitol (MNTL) ratio, were evaluated for their effects on the response variables, disintegration time, hardness, friability and wetting time, of the resulting FDTs. By employing Central Composite Design (CCD) methodology, the FDTs were optimized to achieve optimum levels of the formulation factors. Results: The desired optimum condition was obtained at 7.82% crospovidone and 70% of 1.56:1 MCC: MNTL ratio, while maintaining AB at 5% level for aesthetic reasons. Under the optimized conditions, the disintegration time, hardness, friability, and wetting time were 14.57 ± 0.53 sec, 7.17 ± 0.82 kg/cm2, 0.311% and 13.14 ± 0.69 sec, respectively. The experimentally observed responses were found to be in close agreement with the predicted values for the optimized formulation. Moreover, the validity of the obtained optimal point was confirmed by the low magnitude of percent prediction error (< 5%). Conclusion: FDTs of SBS were successfully formulated and optimized using CCD employing a combination of a superdisintegrant and a subliming agent.

Objective: The present study was undertaken to develop a rapid, simple, specific and economic ultraviolet (UV) spectrophotometric method for estimating the Salbutamol Sulphate (SS) in pharmaceutical formulations. Methods: The analysis was performed at λ max 276 nm using Sorenson’s isotonic phosphate buffer pH 7 (SIPB pH 7) as blank/diluent. The method was validated by following the analytical performance parameters as suggested by International Conference on Harmonization (ICH) which included accuracy, precision, linearity. Results: The drug follows the beer’s lambert’s law in the concentration range of 12.5-37.5μg/ml and exhibited good correlation coefficient (0.9997) and excellent mean recovery. Percentage RSD for precision and accuracy of the method was found to be less than 2%. This method was successfully applied for the determination of the Salbutamol Sulphate in commercial brands of Indian market and the results were in good agreement with the label claims. The developed method was suitable and specific to the analysis of Salbutamol Sulphate even in the presence of common excipients. Conclusion: The obtained results proved that the validated method can be employed for the routine analysis of Salbutamol Sulphate in bulk as well as in the commercial formulations.

The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystallized mannitol significantly affected aerosolization behavior, with the δ form affording the worst fine particle fraction with both the hydrophilic (9.3 and 6.5%) and the lipophilic (19.6 and 32%) model drugs, while α and β forms behaved in the same manner (11–13% for SS, 53–58% for BUD) and better than lactose (8 and 13% for SS, 26 and 39% for BUD). Recrystallized mannitol, but also PVA and PVP, proved to be safe excipients toward lung cell lines. We concluded that, also for mannitol, the physicochemical properties stemming from different crystal structures represent a tool for modulating carrier-drug interaction and, in turn, aerosolization performance.

Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193–221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R2=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.

The use of physiologically based pharmacokinetic (PBPK) models to support drug product development has become increasingly popular. The in vitro characterization of the materials of the formulation provides valuable descriptors for the in silico prediction of the drug’s pharmacokinetic profile. Thus, the application of an in vitro–in silico framework can be decisive towards the prediction of the in vivo performance of a new medicine. By applying such an approach, this work aimed to derive mechanistic based insights into the potential impact of carrier particles and powder bulk properties on the in vivo performance of a lactose-based dry powder inhaler (DPI). For this, a PBPK model was developed using salbutamol sulphate (SS) as a model drug and the in vitro performance of its low-dose blends (2% w/w) with different types of lactose particles was investigated using different DPI types (capsule versus reservoir) at distinct airflows. Likewise, the influence of various carrier’s particle and bulk properties, device type and airflow were investigated in silico. Results showed that for the capsule-based device, low-dose blends of SS had a better performance, when smaller carrier particles (Dv0.5 ≈ 50 μm) with about 10% of fines were used. This resulted in a better predicted bioavailability of the drug for all the tested airflows. For the reservoir type DPI, the mean particle size (Dv0.5) was identified as the critical parameter impacting performance. Shear cell and air permeability or compressibility measurements, particle size distribution by pressure titration and the tensile strength of the selected lactose carrier powders were found useful to generate descriptors that could anticipate the potential in vivo performance of the tested DPI blends.

The multi-factorial interplay between particle engineering, particle properties, their downstream processability and aerodynamic performance contributes to the overall dry powder inhaler (DPI) performance. Inhalable particles of salbutamol sulphate were prepared by jet-milling and spray drying, characterized, and blended with lactose at low and high drug loads. These were filled into capsules using different process parameters and tested for their in vitro aerosolization performance. Differences were found in the particle interactions of jet-milled and spray dried powders, affecting their downstream processability. Blends of the spray dried particles revealed to be more prone to detachment during processing, resulting in a poorer aerodynamic in vitro performance. A higher drug load further affected the drug interaction with the excipient resulting in weaker carrier attachment and a higher in vitro fine particle fraction. The mean fill weight and blend homogeneity of the filled capsules showed distinct effects in relation to the type of mixture being processed, resulting into variable aerosolization performance results depending on the compression ratio used. By investigating the impact of distinct API properties and drug loadings on all the downstream processability chain, critical parameters needed to be considered in product quality and performance of jet-milled and spray dried drug particles were derived.

Background: A sensitive high-performance thin layer chromatographic (HPTLC) method was developed for simultaneous determination of beclomethasone dipropionate and salbutamol sulphate from inhalation product. Methods: Chromatographic separation was achieved on aluminium plates pre-coated with silica gel G60 F254 as the stationary phase and methanol:ethyl acetate:toluene:ammonia (3:1:3:0.15) as the mobile phase. The densitometric evaluation was carried out at 232 nm. The developed method was validated as per the ICH Q2 (R1) guidelines. Robustness of the proposed method was assessed using experimental design approach, and results were analyzed graphically. The results of sample analysis by proposed HPTLC method and reported HPLC method were statistically compared. Results: The Rf value of salbutamol sulphate and beclomethasone dipropionate was found to be 0.38±0.02 and 0.72±0.02, correspondingly. The response in terms of peak area was linear over the concentration range of 100-500 ng/spot and 200-1000 ng/spot for beclomethasone dipropionate and salbutamol sulphate, individually, with the regression coefficient values greater than 0.99 for both the drugs. The limit of detection and limit of quantification for beclomethasone dipropionate were found to be 27 ng/spot and 84 ng/spot, respectively and for salbutamol sulphate were 40 ng/spot and 112 ng/spot, respectively. The proposed method was found to be statistically insignificant when compared to the reported method. Conclusion: The proposed method is robust, sensitive, accurate and precise. The method can be applied for the simultaneous estimation of beclomethasone dipropionate and salbutamol sulphate from inhalation product.

Objectives: To design a formulation and develop ODTs of AMB hydrochloride and salbutamol sulphate in combination for the treatment of respiratory disorders and perform an in vitro evaluation using superdisintegrants in combination with a suitable binder and excipients. Direct compression was used to prepare the tablets. Materials and Methods: In the present research work, different concentrations of SSG as a superdisintegrant were used to optimize the concentration of SSG in the formulation of ODTs. Different concentrations of MCC and PVP K-30 were also studied along with the optimized SSG concentration. The tablets were evaluated for hardness, friability, weight variation, wetting time, in vitro DT, and percentage drug content uniformity. The optimized formulation was further evaluated in an in vitro release study, and drug-excipient compatibility and accelerated stability study. Results: The optimized concentration of SSG was found as 4% on the basis of the lowest DT. The 1% concentration of MCC was selected as the optimum binder concentration on the basis of the lowest DT. ODTs passed all the quality control tests viz., weight variation, hardness, friability, in vitro DT, drug content (%) and wetting time. The formulation satisfied the requirements of the FDA for rapid-dissolving tablets and allowed more than 85% drug to be released within 30 min. The fourier transform infrared spectroscopy study revealed that there was no interaction between the drug and excipients. The accelerated stability study shows that formulation is quite stable at normal temperature and humidity conditions as well as at extreme temperature conditions. Conclusion: By adopting a systematic formulation approach, ODTs of AMB hydrochloride and salbutamol sulphate in fixed-dose combination can be formulated using superdisintegrants in combination with appropriate binder and excipients; this was found to be economical and industrially feasible.

Objectives: Superdisintegrants play important role in disintegration of orally disintegrating tablets (ODTs). Action of three different superdisintegrants, viz. croscarmellose sodium, sodium starch glycolate and Indion 414, were studied individually or in their binary combinations for their fast disintegrant action in ODTs of salbutamol sulphate prepared by direct compression. Materials and Methods: ODTs were prepared in three different superdisintegrant combinations A, B and C. In each combination, five formulations were prepared with superdisintegrants in ratios 10:90, 25:75, 50:50, 75:25, and 90:10. Three ODT formulations were prepared with single superdisintegrant and two ODT batches were prepared from marketed ODT excipient blends, viz. Prosolv-ODT and F-Melt. Prepared ODT formulations were evaluated and compared for weight variation, hardness, friability, wetting time, disintegration and drug release. Results: All ODTs disintegrated quickly in 32 s or less. ODT formulation F3, containing croscarmellose sodium and sodium starch glycolate, disintegrated very quickly in 19.28±3.11 s. Results of F3 were compared with the batches (F19 and F20) containing marketed coprocessed excipients and found in good agreement for various evaluation parameters. Formulation F20 was hygroscopic, while F3 did not suffer this disadvantage. Conclusion: Thus, we may conclude that superdisintegrants in combinations may offer additive and/or synergistic disintegration possible due to their different mechanism.

Physico-chemical properties of lactose are key factors in adhesive mixtures used as dry powder inhaler (DPI). Despite the abundant literature on this topic, the effect of the polymorphism and pseudo-polymorphism of lactose has been seldom investigated and discussed although often lactose used in DPI is subjected to unit operations, which may alter its solid-state properties. Here, we studied the aerosolization performance of salbutamol sulphate (SS) or budesonide (BUD) formulations by investigating the effect of lactose pseudopolymorphism in ternary (coarse lactose/fine lactose/drug) and binary (coarse lactose/drug) mixtures. An improvement of the aerosolization performance of SS formulations with the increase of the amount of fine micronized lactose up to 30% (fine particle fraction (FPF) = 57%) was observed. Micronized lactose contained hygroscopic anhydrous &alpha, lactose, which converted to &alpha, lactose monohydrate at ambient conditions. This implied that the positive effect of fines on the aerosolization performance decreased and eventually disappeared with the formulation aging. Positive effect on SS deposition was observed also with binary mixtures with anhydrous lactose, whereas the opposite occurred with budesonide-containing formulations. The collected data demonstrated the crucial role of the carrier crystal form on the positive effect of fines on the deposition.

Purpose The performance of carrier-based dry powder inhaler (DPI) formulations can be critically impacted by interfacial interactions driven by tribo-electrification. Therefore, the aim of the present work was to understand how distinct API particle characteristics affect the charging behaviour of blends intended for DPI delivery. Methods Salbutamol sulphate (SBS) particles engineered via spray-drying and jet milling were used as model APIs. D-mannitol was selected as a model carrier. The materials were characterized concerning their different particle properties and their charge was analysed alone and in blends before and after flow over a stainless-steel pipe. Results The spray-dried SBS (amorphous and spherical) charged positively and to a higher extent than jet milled SBS (crystalline and acicular) that charged negatively and to a lower extent. D-mannitol charged positively and to a higher extent than the APIs. All drug-excipient blends charged negatively and differences were found between the spray-dried and jet milled SBS blends at 2% and 5% drug loads. Conclusions It was demonstrated how distinct solid-states, particle shape, size and morphology as well as different water contents of the different materials can affect tribo-charging. For their binary blends, the amount and nature of fines seem to govern inter-particle contacts critically impacting charge evolution. Electronic supplementary material The online version of this article (10.1007/s11095-019-2612-9) contains supplementary material, which is available to authorized users.

The aim of this research was to develop and evaluate gastric floating tablets of salbutamol sulphate. The oral delivery of anti-asthmatic salbutamol sulphate tablets were facilitated by preparing floating dosage form which could increase its absorption in the stomach by increasing the gastric residence time of the drug. Floating tablets were formulated by using different polymers like carbopol, xanthan gum, HPMC-K4 MCR and HPMC- K100 MCR with different proportions. A comparative study of normal effervescent tablets of salbutamol sulphate had also been done. The prepared tablets were evaluated for all their physicochemical properties and in vitro buoyancy study. In vitro dissolution studies of the formulations were done in pH 6.8 phosphate buffer using USP apparatus 2 (paddle method) at 50 rpm. Percent drug release of the formulations (F-1 to F-11) was from 87.34%- 99.12% after 12 hours. From the results, F-11 was selected as an optimized formulation based on 12 h drug release which showed minimal floating lag time and maximum floating time. On the other hand, 100% drug was released within 2 hours from the F-12 of effervescent salbutamol sulphate tablets in which polymer was absent while gas generating sodium bicarbonate and citric acid were present. The results of the study were consistent and may encourage formulating similar dosage form with other drugs.Dhaka Univ. J. Pharm. Sci. 15(2): 203-208, 2016 (December)

Preterm labor is a major cause of infant serious illness and deaths in the world. Salbutamol is a betamimetic tocolytic drug used to arrest preterm labor. It is given as I.V. infusion then maintenance of treatment is achieved by oral tablets. This study aims to formulate bioadhesive vaginal sustained core–in-cup salbutamol sulphate tablets to improve patient compliance and overcome the side effects of invasive and non-invasive conventional salbutamol formulations. Vaginal bioadhesive sustained core–in-cup salbutamol sulphate tablets were evaluated for their physicochemical properties, bioadhesion properties and dissolution test. All formulations showed acceptable hardness, friability, weight variation and drug content values. F4 (HEC as core), F5 (PEG as core) and F6 (Carbopol 934 as core) and Carbopol 934 as mucoadhesive cup fulfill the desired criteria of both prolonged-release and maximum bioadhesive properties. F4, F5&F6 were selected for stability study. F6 showed better pharmacokinetics parameters (Tmax, AUC (0-24) & t ½) than that of the marketed product (Ventolin®). F6 caused a significant delay of labor than that of the marketed product (Ventolin®) using uterine contraction model. So, it could be concluded that a promising vaginal bioadhesive sustained core–in-cup salbutamol sulphate tablet was successfully developed and can provide effective treatment of preterm labor.

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3 2 factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of ‘matched’ SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.

This study investigates engineered carrier, as well as engineered API particles, and shows that there are distinct performance indicators of particle engineering for carrier-based dry powder inhalers (DPIs). Spray dried (SDSS) and jet-milled (JMSS) salbutamol sulphate (SS) was blended with untreated α-lactose monohydrate (LAC_R) and α-lactose monohydrate engineered (LAC_E). Subsequent capsule filling was performed with different process settings on a dosator nozzle capsule filling machine in order to reach a target fill weight of 20-25 mg. To evaluate the performance of the different mixtures, in vitro lung deposition experiments were carried out with a next generation impactor, the emitted dose (ED) and fine particle fraction (FPF) were calculated based on the specification of the European pharmacopoeia. The FPF of micronised powder blends is significantly higher (20%) compared to the FPF of spray dried blends (5%). Compared to API engineering, carrier engineering had a positive effect on the capsule filling performance (weight variability and mean fill weight) at lower compression ratios (setting 1). Results further showed that higher compression ratios appear to be beneficial in terms of capsule filling performance (higher fill weight and less fill weight variation). Concluding, it can be stated that the carrier engineering, or generally carrier properties, govern downstream processing, whereas the API engineering and API properties govern the aerosolisation performance and thereby significantly affect the dose delivery to the lungs.

Electrostatic forces have been claimed to be a mechanism for aerosol deposition in the lungs. However, the extent of its influence on aerosol performance is not clear, particularly for carrier-drug formulations.To prepare lactose-salbutamol powder blends, varying in blend ratio, and identify any relationships between salbutamol dose, electrostatic characteristics and in vitro aerosol performance.Decanted lactose and micronized salbutamol sulfate was mixed to produce five blends (equivalent to 50, 100, 200, 300 and 400 µg salbutamol per 33 mg of powder). 33 ± 1 mg of a blend was loaded into a Cyclohaler™ and dispersed into the electrical Next Generation Impactor (eNGI) at an air flow rate of 60 L/min. This was conducted in triplicate for all five lactose-salbutamol blends.Fine particle fraction increased with salbutamol dose, from 5.89 ± 1.42 to 21.35 ± 2.91%. Specific charge (charge divided by mass) distributions for each blend were greatest in magnitude for the 50 µg blend and similar in magnitude between all other blends. However, in eNGI Stage 1 (8.06 µm), specific charge decreased from 100 µg (-170.4 ± 45.8 pC/µg) to 400 µg (-10.0 ± 9.1 pC/µg).The improvement in fine particle fraction with increased salbutamol dose was indicative of fine drug binding to high and low energy sites on the lactose carrier surface. This finding was supported by electrostatic charge results, but the aerosol charge itself was not found to influence aerosol performance by electrostatic forces.

To evaluate the use of thermal ink-jetting as a method for dosing drugs onto oral films.A Hewlett-Packard printer cartridge was modified so that aqueous drug solutions replaced the ink. The performance of the printer as a function of print solution viscosity and surface tension was determined; viscosities between 1.1 and 1.5 mm(2) s(-1) were found to be optimal, while surface tension did not affect deposition. A calibration curve for salbutamol sulphate was prepared, which demonstrated drug deposition onto an acetate film varied linearly with concentration (r(2) = 0.9992). The printer was then used to deposit salbutamol sulphate onto an oral film made of potato starch.It was found that when doses were deposited in a single pass under the print head, then the measured dose was in good agreement with the theoretical dose. With multiple passes the measured dose was always significantly less than the theoretical dose. It is proposed that the losses arise from erosion of the printed layer by shearing forces during paper handling. The losses were predictable, and the variance in dose deposited was always less than the BP limits for tablet and oral syrup salbutamol sulphate preparations.TIJ printing offers a rapid method for extemporaneous preparation of personalized-dose medicines.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

Purpose: The crystallization and structural integrity of micron-sized inhalable salbutamol sulphate particles coated with l-leucine by different methods are investigated at different humidities. The influence of the l-leucine coating on the crystallization of salbutamol sulphate beneath the coating layer is explored.Methods: The coated particles are prepared by an aerosol flow reactor method, the formation of the l-leucine coating being controlled by the saturation conditions of the l-leucine. The coating is formed by solute diffusion within a droplet and/or by vapour deposition of l-leucine. The powders are humidified at 0%, 44%, 65% and 75% of relative humidity and the changes in physical properties of the powders are investigated with dynamic vapour sorption analysis (DVS), a differential scanning calorimeter (DSC), and a scanning electron microscope (SEM).Results: Visual observation show that all the coated particles preserve their structural integrity whereas uncoated salbutamol sulphate particles are unstable at 65% of relative humidity. The coating layer formed by diffusion performs best in terms of its physical stability against moisture and moisture-induced crystallization. The degree of crystallization of salbutamol in the as-prepared powders is within the range 24–35%. The maximum degree of crystallization after drying ranges from 55 to 73% when the salbutamol crystallizes with the aid of moisture. In addition to providing protection against moisture, the l-leucine coating also stabilizes the particle structure against heat at temperatures up to 250°C.Conclusion: In order to preserve good flowability together with good physical stability, the best coating would contain two l-leucine layers, the inner layer being formed by diffusion (physical stability) and the outer layer by vapour deposition (flowability).

Salbutamol sulphate nanoparticles have been simultaneously prepared and coated with L-leucine in the gas phase. Three different ways of coating can be separated based on the operation temperatures used in an aerosol flow reactor. Below the temperature of L-leucine sublimation, formation of the L-leucine layer on the core particle surface takes place via diffusion of L-leucine molecules on the droplet surfaces during droplet drying. At intermediate temperatures, the extent of sublimation of L-leucine depends notably on the concentration, and thus partial evaporation was expected. The L-leucine coating was solely formed via vapor deposition at high reactor temperatures when complete sublimation of L-leucine was obtained. The geometric mean diameter of the core salbutamol particles was approximately 65 nm. In general, particle size increased with the addition of L-leucine. The size distribution remained the same or broadened when the coating layer of the particles was formed via surface diffusion whereas notable narrowing of the distribution was observed when the coating was formed via vapor deposition. Upon desublimation and heterogeneous nucleation on the surfaces of smooth, spherical core particles, L-leucine formed a discontinuous coating with leafy crystals a few nanometers in size.

A time dependent pulsed release system consisting of an effervescent core surrounded by consecutive layers of swelling and rupturable polymers was prepared and evaluated. The cores containing salbutamol sulphate as bioactive agent were prepared by direct compression method using different ratios of microcrystalline cellulose and effervescent agent and then coated sequentially with an inner swelling layer containing a hydrocolloid, hydroxypropylmethylcellulose E5 and an outer rupturable layer having Eudragit RL/RS (1:1). The effects of various processing and formulative parameters on the performance of system were studied. The rupture and dissolution tests were studied using the USP paddle method at 50 rpm in 0.1 N HCl and phosphate buffer pH 6.8. The lag time of the drug release decreased by increasing the inner swelling layer and increased by increasing the rupturing layer level. All the results obtained in the present study suggest that osmotic pumping effect was involved which eventually lead to the drug release.

Lactose monohydrate for inhalation is commonly produced by sieving out customer-specific size fractions of a crystallized bulk material of lactose. It was the aim of this study to investigate the influence of the raw material on the physico-chemical properties of the inhalation grade lactose and on the efficacy of powders for inhalation produced from these batches. The selected raw material lactose batches differed in the size distribution characteristics, the fines and the agglomerate content. These differences in the raw material could also be found to a smaller extent in the intermediate products and could not be completely levelled out in the final inhalation grade lactose. Efficiency testing was done using salbutamol sulphate in two different concentrations (drug-to-carrier ratio of 1:36 and 1:400) as a model drug; the powder blends were delivered using the Aerolizer and the Easyhaler device. With the high drug load, nearly no differences could be observed between both the delivery systems and the different produced lactose batches. The fine particle fraction (FPF) (%5 microm) was on a high level of39% in all cases. With the low drug load significant differences between the devices and the lactose batches were found. The FPF was distinctly reduced to 15-30%, with the Easyhaler generating a higher fraction of fine particles than the Aerolizer device. Although the observed differences between the lactose batches could not be linked to one specific physico-chemical parameter determined for the carrier, they led to the conclusion that the differences between the test batches of inhalation grade lactose especially manufactured for this study can affect the functionality of an inhalation powder. The effects are significantly smaller with high drug load formulations than using a low drug concentration.

Purpose. Microthermal analysis is a recently introduced thermoanalytical technique whereby discrete regions of complex samples may be scrutinized at micron or submicron resolution. In this investigation, the novel use of the technique to study individual powder particles is described.

The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols’ behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.

Objective: Salbutamol sulphate (SBS) and doxophylline (DOX) was used for the treatment of asthma and bronchitis. In the present study, two simple, accurate, precise, reproducible and economical UV-spectroscopic methods (A and B) for simultaneous estimation of SBS and DOX in tablet dosage form have been developed. Methods: In the present study the simultaneous estimation of SBS and DOX was carried out by two methods. Method A employs solving of simultaneous equations based on the measurement of absorbance at two wavelengths, 272 nm and 276 nm which are the 𝜆 max values of SBS and DOX respectively in phosphate buffer (pH 7.4). Method B is based on the principle of Q -Analysis where in, absorbance was measured at 225 nm (iso-absorptive point, 𝜆 1 ) and 276 nm (𝜆 max of DOX, 𝜆 2 ) in phosphate buffer (pH 7.4). Results: Both SBS and DOX shows linearity at all the selected wavelengths and obeys beer’s law in the concentration range of between 0.2-1.6𝜇g/ml and 0.1-3.5μg/ml at 276 nm; 0.2-1.6 µg/ml and 0.1-4.5 µg/ml at 272 nm and 0.2-2.0µg/ml and 0.2-3.5μg/ml at iso-absorptive point 225 nm. Recovery studies for SBS and DOX were performed and the percentage recovery for both the drugs was obtained in the range of 97.45-98.63% (Method A) and 97.49–98.87 % (Method B) confirming the accuracy of the proposed method. Conclusion : Both the methods showed good reproducibility and recovery with % RSD less than 2. Statistical validation of the data shows that the proposed methods can be successfully applied for the routine analysis of drugs in commercial tablets. Hence, it could be used in the analysis of laboratory samples and marketed formulations containing these two drugs in combined dosage form without the interference of common excipients.

A simple, selective, and accurate high performance liquid chromatographic method for the determination of cephalexine, cefotaxime, and salbutamol sulphate was developed. The suggested method uses ODS column with methanol-phosphate buffer (pH 7) 6:4 as a mobile phase. The mean percentage recovery ranged from 97.4 to 98.8. The proposed method was applied to the determination of the selected drug in some pharmaceutical preparations. The statistical analysis of the results obtained was compared favourably with those given with the official method.

The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.

CONTEXT: Salbutamol sulphate is widely used as bronchodilator for the treatment of asthma. Its use is limited by the relatively short duration of action and hence sustained delivery of salbutamol sulphate offers potential benefits to patients. OBJECTIVE: This study explores the preparation of lipid microparticles (LMs) as biocompatible carrier for the prolonged release of salbutamol sulphate. MATERIALS AND METHODS: The LMs were produced using different lipidic materials and surfactants, by classical melt emulsification-based methods (oil-in-water and water-in-oil-in-water emulsions) and the spray congealing technique. RESULTS: For the LMs obtained by melt emulsification a lack of release modulation was observed. On the other hand, the sustained release of salbutamol sulphate was achieved with glyceryl behenate microparticles prepared by spray congealing. These LMs were characterized by scanning electron microscopy, X-ray diffractometry and differential scanning calorimetry. The drug loading was 4.72% (w/w). The particle size distribution measured by laser diffraction and electrical zone sensing was represented by a volume median diameter (Dv(50)) of 51.7-71.4 µm. Increasing the atomization air pressure from 4 to 8 bar produced a decrease of the Dv(50) to 12.7-17.5 µm. CONCLUSIONS: Incorporation of the hydrophilic salbutamol sulphate into LMs with sustained release characteristics was achieved by spray congealing.

The potential of excipient coating to enhance aerosol performance of micronized drugs in carrier excipient-drug blends, used in dry powder inhalers, was investigated. Both EC (ethyl cellulose) and PVP (polyvinylpyrrolidone) were used as coating agents. Carriers were prepared via sieve fractioning followed by spray drying, with and without polymer additive. Each uncoated and coated carrier salbutamol sulphate (SS) blended systems were evaluated for particle size, morphology, drug carrier adhesion and aerosolisation performance, after blending and storage for 24h. All carrier-based systems prepared had similar particle sizes and morphologies. The surface chemistries of the carriers were significantly different, as was drug-carrier adhesion and aerosolisation performance. Particle adhesion between SS and aerosol performance (fine particle fraction; FPF) followed the rank: PVP coated>un-coated>EC coated lactose. This rank order could be attributed to the surface energy measured by contact goniometry and related to the chemistry of lactose and each polymer. Storage did not significantly affect aerosol performance, however a rank increase in mean FPF value was observed for uncoated and EC coated lactose. Finally, the net electrostatic charge across the aerosol cloud indicated that the EC coated lactose transferred less charge to SS particles. The performance of each carrier system could be attributed to the carrier surface chemistry and, in general, by careful selection of the coating polymer, drug-carrier adhesion, electrostatic charge and aerosol performance could be controlled.

A reversed-phase ion-pair high-performance liquid chromatography assay was developed for the simultaneous determination of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate and terbutaline sulphate in nebulizer solution. Chromatographic separation was achieved with a Nova-Pak C18 4 microns 10 cm x 8 mm i.d. Radial-pak cartridge inside a Waters RCM 8 x 10 compression module using ternary gradient analysis. Detection was performed using UV detection at 220 nm. The standard curves were linear over the following ranges: ipratropium bromide 20.8-250.0 micrograms ml-1, fenoterol hydrobromide 27.8-500.0 micrograms ml-1, salbutamol sulphate 34.7-2500.0 micrograms ml-1 and terbutaline sulphate 69.5-2500 micrograms ml-1. Inter-day and intra-day relative standard deviations for each compound ranged from 4.5-5.2% and 3.5-3.9%, respectively. The assay procedure was developed to allow the accurate determination of constituents in various combinations of nebulizer solution, as well as for stability indicating purposes. This provides a convenient means of testing long-term compatibility and stability following the post-manufacture mixing of commonly used nebulized preparations.

The aim of the study described was to develop prolonged-release press-coated tablets of salbutamol sulphate from which drug release would increase with time. The bioavailability of the formulation considered best was then studied in man. The tablets, each consisting of a core and a coat, were prepared using a compression-coating technique. Salbutamol sulphate was divided between the core and the coat in the ratio 2:1 or 1 : 2. Different viscosity grades and amounts of hydroxypropylmethylcellulose (HPMC) were used in the coat. When HPMC K100 was used, release of salbutamol sulphate from tablets with 2/3 of the drug in the core increased with time. The release patterns obtained with 1/3 of the drug in the core were biphasic. With other HPMC grades, the release patterns were best described by zero-order kinetics with 2/3 of the drug in the core and square-root-of-time kinetics with 1/3 of the drug in the core. For all formulations, an increase in the amount of HPMC decreased drug release rate. In man the only statistically significant difference in bioavailability parameters between the test formulation and the commercial reference preparation related to C max values.

Salbutamol sulphate (SS) can be analysed very accurately by second-derivative ( 2 D) UV spectroscopy at concentrations between 1 and 80 μg/ml, in the presence of fairly high levels of bovine albumin. The non-derivatised ( 0 D) UV-spectroscopic analysis of salbutamol sulphate is severely hindered due to interference by albumin while in 4 D, Beer-Lambert's law is not obeyed between 1 and 8 μg/ml.

Mucoadhesive patch releasing the drug in the oral cavity at predetermined rate may present distinct advantages over traditional dosage forms such as tablets, gels and solutions. The present study was concerned with the preparation and evaluation of mucoadhesive buccal patches for the controlled systemic delivery of Salbutamol sulphate to avoid first pass hepatic metabolism. The developed patches were evaluated for the physicochemical, mechanical and drug release characteristics. The patches showed desired mechanical and physicochemical properties to withstand environment of oral cavity. The in-vitro release study showed that patches could deliver drug to the oral mucosa for a period of 7 h. the patches exhibited adequate stability when tested under accelerated conditions.

Gelatin has been found to interfere in the accurate estimation of salbutamol sulphate by visible UV spectroscopy. UV-spectrophotometric determinations by zero-, second- and fourth-orders were carried out for aqueous solutions containing a fixed concentration of salbutamol sulphate (20 μg/ml) and varying concentrations of gelatin (1–8 μg/ml; 10–80 μg/ml). Results of observations show that as the order of the derivative is increased, the spectral interference by gelatin is decreased significantly.

The decomposition of salbutamol sulphate (albuterol sulphate) was studied in the pH range 1.9–8.8 at 65°C. The decomposed salbutamol sulphate solutions were discoloured and contained a precipitate. Depending on the pH of the solution, one to four major and several minor decomposition products were formed. The rate of decomposition was followed by RP-HPLC with UV detection. The decomposition of salbutamol in aqueous solution obeyed apparent first-order kinetics with respect to salbutamol sulphate. The reaction rate increased with increasing initial drug concentration and elevated temperatures. The maximum stability of salbutamol in aqueous solution occurred at a pH of about 3.5.

Controlled release tablet of Salbutamol has been shown to be clinically superior to the standard 4 mg Salbutamol tablets given 3–4 times daily. Salbutamol-Sulphate sustained release tablets based on two marketed polymers, Eudragit and Methocel, is presented here. Effect of water insoluble diluents on in vitro drug release was evaluated.

The influence of storage humidity on the aerosolisation efficiency of micronised and supercritical fluid salbutamol sulphate formulations (containing a lactose carrier) were investigated using the twin stage impinger (TSI). Storage humidity had a significant effect on the aerosolisation efficiency of both micronised and solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate (ANOVA P0.05), suggesting capillary interactions to be an important factor when considering formulation performance. Furthermore, significant differences between the aerosolisation performance of micronised and SEDS salbutamol sulphate were observed at elevated humidities (63% RH) (Fishers pairwise P0.05). It is suggested that such variations may be due to differences in physical stability of the micronised and SEDS produced material. Dynamic vapor sorption, and atomic force microscopy (AFM) phase imaging suggested the micronised material to contain amorphous content that was most likely present on the micronised particulate surfaces. Thus, at high humidity, surface amorphous regions may have the ability to re-crystallize and effectively 'fuse' to the lactose carrier surface. This would potentially reduce the ability for the micronised material to be aerosolized and thus result in a greater decrease in FPF when compared to SEDS produced material at equivalent RH.

A simple reverse phase liquid chromatographic method has been developed and subsequently validated for simultaneous determination of salbutamol sulphate and bromhexine hydrochloride. The separation was carried out using a mobile phase consisting of acetonitrile, methanol and phosphate buffer, pH 4 in the ratio 60:20:20 v/v. The column used was SS Wakosil-II C-18 with a flow rate of 1 ml/min and UV detection at 224 nm. The described method was linear over a concentration range of 10-110 µg/ml and 20-140 µg/ml for the assay of salbutamol sulphate and bromhexine hydrochloride, respectively. The mean recovery was found to be 95-105% for salbutamol sulphate and 96.2-102.1% for bromhexine hydrochloride when determined at five different levels.

Asthma is an inflammatory disorder that results in the obstruction of air pathways and causes difficulty in breathing. Amongst the currently available means of treatment, oral dosage forms are associated with lag time and delayed onset of action. However, aerosols and parenterals have rapid onset of action but strongly affect patient compliance. Thus, an attempt was made to improve the onset of action of bronchodilator used commonly in the treatment of asthma. Fast dissolving tablets of salbutamol sulphate were prepared using sublimable ingredients. Selection of the filler also had an important role in deciding the disintegration time. Evaluation of the tablets showed that all the tablets were found to be within official limits and the disintegration time for the formulations ranged from 5 s to 40 s. Amongst all, the formulation containing microcrystalline cellulose and ammonium bicarbonate showed the least disintegration time of 5 s.

Isothermal microcalorimetry has been used to monitor the recrystallisation of spray-dried salbutamol sulphate. The drug recrystallises in water vapour, by a cooperative process. The cooperative nature demonstrates that the water must first absorb to saturate the entire powder bed before recrystallisation occurs. Consequently, recrystallisation is slower for low humidities, due to a slower arrival of water vapour. The data have been compared with previous data for recrystallisation of spray-dried lactose. The heat change for the crystallisation was significantly lower for salbutamol sulphate than for lactose. In terms of apparent enthalpy of crystallisation, the large exothermic responses are indicative of the fact that the crystal form is the thermodynamically stable state. The salbutamol which had been recrystallised at the lower humidities showed that the process, whilst being rapid, was discontinuous. In each case, the exothermic recrystallisation was followed by an endothermic response for the expulsion of water as the amorphous region recrystallised. There was a repeating sequence of crystallisation, followed by water expulsion, followed by further recrystallisation. With each repeat of the cycle the responses decreased in size. This ability to follow crystallisation in real time provides a novel insight into the process.

The present work deals with the development of controlled release tablets of salbutamol sulphate (SS) using graft copolymers of methyl methacrylate (St-g-PMMA and Ast-g-PMMA) on starch and acetylated starch. Formulations were evaluated for physical characteristics like hardness, friability, drug release, drug content and weight variations, which fulfilled all the official requirements of tablet dosage form. The release rates from formulated matrix tablets were studied at SGF (pH 1.2) followed by SIF (pH 6.8). Drug release from the graft copolymer based tablets was found to be sustained upto the 14 h with >75% drug release. The in-vitro release study showed that the graft copolymer based matrix formulations (F3 & F4) exhibited highest correlation value ( r 2 ) for higuchi kinetic model and Korsmeyer's model with n values between 0.61 and 0.67 proved that release mechanisms were governed by both diffusion and erosion mechanism. There was no significant difference in the pharmacokinetic parameters ( t max , C max , AUC, K e , and t 1/2 ) of the graft copolymers matrices and HPMC K100M matrix tablets, indicating their comparable sustained release effect. The potential of graft copolymers to sustain the drug release is well supported by in-vivo pharmacokinetic studies and their adequate physicochemical properties make them promising excipients for controlled drug delivery system.